Investigating the cell death mechanisms and effects of caspase inhibition in deep pressure ulcers

xiv, 130 leaves : ill. ; 30 cm.PolyU Library Call No.: [THS] LG51 .H577M HTI 2011 TengThe molecular mechanisms that contribute to the pathogenesis of deep pressure ulcer remain to be elucidated. The purpose of this study was to examine the role of apoptosis and autophagy in muscle breakdown as induced by prolonged, moderate compression in a rat model. Apoptotic signaling components, autophagy regulatory factors and cellular stress markers including Bax, Bcl-2, caspases, XIAP, AIF, EndoG, p53, Beclin-1, Atg genes, LC3, FoxO3, Akt, HSP70, MnSOD and CuZnSOD were assessed. We demonstrated the opposing responses of apoptosis and autophagy to moderate compression in muscle. The incidence of apoptosis, activation of pro-apoptotic signaling and disruption of oxidative balance were evident in the skeletal muscle following sustained compression. Intriguingly, autophagy was found to be downregulated in this in vivo compression model. Intrinsic and extrinsic apoptotic pathways responded selectively to different experimental circumstances of compressions and apoptotic alterations were found in the muscles following prolonged compression. In general, these findings are consistent with the overall hypothesis that cellular apoptosis and autophagy are involved in the pathogenesis of pressure-induced muscle pathology. We demonstrated that apoptotic and autophagic changes preceded pathohistological changes in skeletal muscle in response to prolonged moderate compression, suggesting the early and causative event of apoptosis and autophagy in compression-induced muscle pathology. Caspases have been considered potential molecular targets to attenuate apoptotic response in tissues. Our findings further demonstrated that z-VAD-fmk, a caspase inhibitor, was effective in alleviating the compression-induced pathohistology and apoptosis in muscle while the basal autophagic signaling level was maintained. These findings supported the idea that pharmacological inhibition of apoptosis was effective in alleviating muscle damage as induced by prolonged compression. Our findings provide the basis for future research on drug or intervention development targeting apoptotic cell death in treating and preventing compression-associated muscle disorders.Department of Health Technology and InformaticsM.Phil., Dept. of Health Technology and Informatics, The Hong Kong Polytechnic University, 201